# CCR5 determinants for the HIV transmitted founder phenotype

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $193,125

## Abstract

ABSTRACT
HIV is naturally transmitted as a virus swarm, which establishes infection via only one or few transmitted/founder
(T/F) viruses. Several observations strongly indicate that T/F viruses are non-randomly favored for productive
transmission via shared signature genotypic and phenotypic characteristics. Current knowledge regarding Env-
coreceptor interactions suggest innovative concepts to explain the T/F phenotype. T/F virus envelopes of all
subtypes preferentially use the CCR5 coreceptor for entry in vitro and in vivo. Yet cell surface CCR5 is expressed
in multiple functional and antigenic forms with differential sensitivity to the antiretroviral CCR5 antagonist
maraviroc (MVC); affinity for natural chemokine ligands, and/or reactivity with anti-CCR5 monoclonal antibodies
(mAbs). Further, the abilities of various anti-CCR5 mAbs to inhibit CCR5 interactions with either tagged soluble
gp120s or pseudoviruses vary according to virus strain and target cell-type. Collectively, these findings prompt
the central hypothesis for this exploratory project: as a class, T/F viruses utilize signature CCR5 subpopulation(s)
that potentially favor more efficient entry and virus replication. Tests of this hypothesis will exploit how active
infection downregulates a “footprint” in the surface CCR5 population, distinguishing which subsets have been
engaged by HIV. We recently reported how innovative superresolution optical imaging methods reflect CI virus
use of distinct antigenic CCR5 forms. The two specific aims of this project will employ similar approaches to
generate an unprecedented view of T/F coreceptor usage and entry on primary cells (human monocytes,
lymphocytes and CD4+ T cells). The definition of “T/F CCR5” usage will impact HIV prevention/treatment efforts
by informing the development of more potent and selective CCR5-based interventions and by elucidating
complementary aspects of Env structure/function that confer coreceptor selectivity and the T/F phenotype. Such
features can be explored by molecular methods and translated to HIV vaccine design.

## Key facts

- **NIH application ID:** 10877909
- **Project number:** 5R21AI174847-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Alonso Heredia
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $193,125
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877909

## Citation

> US National Institutes of Health, RePORTER application 10877909, CCR5 determinants for the HIV transmitted founder phenotype (5R21AI174847-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877909. Licensed CC0.

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